tbuckley/cabot-search huggingface dataset:
Overcoming the cellular barriers and beyond: Recent progress on cell penetrating peptide modified nanomedicine in combating physiological and pathological barriers
Authors: Yingke Liu, Zhihe Zhao, Man Li
Journal: Asian Journal of Pharmaceutical Sciences (2022)

The complex physiological and pathological conditions form barriers against efficient drug delivery. Cell penetrating peptides (CPPs), a class of short peptides which translocate drugs across cell membranes with various mechanisms, provide feasible solutions for efficient delivery of biologically active agents to circumvent biological barriers. After years of development, the function of CPPs is beyond cell penetrating. Multifunctional CPPs with bioactivity or active targeting capacity have been designed and successfully utilized in delivery of various cargoes against tumor, myocardial ischemia, ocular posterior segment disorders, etc. In this review, we summarize recent progress in CPP-functionalized nano-drug delivery systems to overcome the physiological and pathological barriers for the applications in cardiology, ophtalmology, mucus, neurology and cancer, etc. We also highlight the prospect of clinical translation of CPP-functionalized drug delivery systems in these areas.
S222: MATURE T AND NK CELL LYMPHOMAS CLASSIFIED ACCORDING TO 2016 WHO CLASSIFICATION. A REPORT OF THE INTERNATIONAL PROSPECTIVE T-CELL PROJECT 2.0.
Authors: M. Federico, Y. Stepanishyna, T. Skrypets, C. S. Chiattone, M. H. Prince, A. Pavlovsky, A. Lymboussakis, M. Manni, M. Civallero, C. A. de Souza, E. A. Hawkes, L. Fiad, R. Nair, I. Kriachok, F. Hitz, O. Kostina, C. Tomuleasa, A. Guarini, S. Luminari
Journal: HemaSphere (2022)

Background: Mature T and NK-cell lymphomas represent a heterogeneous group of rare lymphoid disorders arising from mature T cells of post-thymic origin. In 2018 the International T-cell non-Hodgkin’s Lymphoma Study Group launched the T-cell Project 2.0. Here we report the distribution of cases of PTCLs registered in the study, based on the diagnosis made locally according to the WHO 2016 classification, and some preliminary information on treatment and outcome. Aims: The aim of the study is a better understanding of this group of rare disorders, capturing a real-life snapshot of the evolving landscape of T-cell lymphoma biology, treatment strategies, and outcome. Methods: The T-cell Project 2.0 (ClinicalTrials.gov Identifier: NCT03964480) is a prospective, longitudinal, international, observational study of patients with PTCLs. Results: Between October 2018 and February 2022, 901 patients with newly diagnosed PTCL were registered by 94 active centers across 17 countries. Distribution of cases according to different subtypes is reported in Figure 1. Overall, the most frequent 6 subtypes account for 93% of cases, and the remaining 7% was represented by few cases of 12 different subtypes. Of note, only 9 cases have been classified according to entities not considered in the previous WHO 2008 classification. With respect to clinical presentation, the median age at diagnosis was 56 years (18-93), 57.4% of the patients were male, the presence of systemic symptoms was reported in 31% of cases, 8.9% had ECOG-PS 3-4, 71% advanced disease and 35.4% bone marrow involvement. At time of data lock, 831 cases had information on initial therapy. Overall, 731 patients (88%) were treated with combination chemotherapy and 125 (15%) were consolidated with high dose therapy and stem cell transplantation. After a median follow-up of 20 months, the 2-year PFS and OS were 49% and 57%, respectively. For patients with PTCL-NOS, AITL, ENKTL, ALCL ALK- and ALCL ALK+, a comparison in terms of PFS was performed for those enrolled in the TCP2 and in the previous TCP1. Interestingly, a statistically significant difference (p=0.009) was observed, with 2-year PFS of 50% and 45% for patients enrolled in the TCP2 and TCP1, respectively. Image:Summary/Conclusion: Regardless the difficulties linked to the COVD-19 pandemic, the TCP2 is recruiting very well and allow us in better understanding the outcome of patients with PTCL classified according to the 2016 WHO in the real world. Moreover, our data show that some improvement in the curability of patients affected by PTCL is emerging.
Cortisol Levels During Acute Illnesses in Children and Adolescents
Authors: Mohammad Rezai, Catherine Fullwood, Beverly Hird, Meghna Chawla, Lesley Tetlow, Indraneel Banerjee, Leena Patel
Journal: JAMA Network Open (2022)

<h3>Importance</h3> Endogenous cortisol levels in children and adolescents during acute illnesses can contribute to the evidence base required to optimize glucocorticoid (GC) stress doses for children and adolescents known to have GC deficiency. <h3>Objective</h3> To identify endogenous cortisol levels during a range of acute illnesses in children and adolescents without GC deficiency from published evidence. <h3>Evidence Review</h3> CINAHL, Cochrane Library, Cochrane Database of Systematic Reviews, Embase, and MEDLINE were searched for studies published between January 1, 2000, and June 30, 2020. Two reviewers independently identified relevant studies. Differences were resolved by joint discussion. Inclusion criteria were common acute illnesses, age from 1 month to 18 years, and basal blood cortisol levels obtained within 48 hours of presentation. Studies with fewer than 5 participants and those that included participants known to have GC deficiency or a history of treatment that could affect cortisol levels were excluded from the review. Data for predefined fields were extracted and independently checked by separate pairs of reviewers. Overall weighted means and pooled SDs for cortisol levels were calculated. <h3>Findings</h3> All 15 studies included were hospital based and included 864 unique participants: 14 studies were prospective observational studies, 1 was part of a trial, and 5 included control individuals. Mean cortisol levels were higher in all participants with an acute illness (n = 689) than in controls (n = 175) (difference in weighted means, 18.95 μg/dL; 95% CI, 16.68-21.22 μg/dL). Cortisol levels were highest in patients with bacterial meningitis (weighted mean [pooled SD], 46.42 [22.24] μg/dL) and were more than 3-fold higher in the group with severe gastroenteritis (weighted mean [pooled SD], 39.64 [21.34] μg/dL) than in the control group. Among the subgroups with sepsis, those with shock had lower cortisol levels than those without shock (weighted mean [pooled SD], 27.83 [36.39] μg/dL vs 37.00 [23.30] μg/dL), but levels in nonsurvivors did not differ from levels in survivors (weighted mean [pooled SD], 24.89 [51.65] μg/dL vs 30.53 [30.60] μg/dL). <h3>Conclusions and Relevance</h3> This systematic review found that, in children and adolescents without GC deficiency, circulating cortisol levels were higher during acute illnesses than those in controls and also varied across a range of acute illnesses. Whether these levels need to be achieved with exogenous GC stress doses tailored according to the nature and severity of the illness in children and adolescents with GC deficiency warrants investigation.
S117: EVI1 DRIVES LEUKEMOGENESIS THROUGH ABERRANT ERG ACTIVATION
Authors: J. Schmoellerl, I. Barbosa, M. Minnich, F. Andersch, L. Smeenk, M. Havermans, T. Eder, T. Neumann, J. Jude, M. Fellner, A. Ebert, M. Steininger, R. Delwel, F. Grebien, J. Zuber
Journal: HemaSphere (2022)

Background: Chromosomal rearrangements leading to overexpression of EVI1 (MECOM) on chromosome 3q26 define a distinct subtype of acute myeloid leukemia (AML) that is associated with chemotherapy resistance and a 2-year survival of <10%. While genetic events driving aberrant expression of EVI1 are increasingly understood, the molecular functions of EVI1 that drive leukemogenesis are unclear, which has so far precluded the development of targeted therapeutics. Aims: We aimed to elucidate transcriptional programs that are maintained by aberrant EVI1 expression and to systematically identify vulnerabilities of EVI1-driven AML. Methods: We developed a panel of mouse models that recapitulate phenotypic and transcriptional hallmarks of patients suffering from EVI1-driven AML, allow tetracycline-controllable EVI1 expression and the functional interrogation of genetic targets using CRISPR/Cas9. We mapped transcriptional programs upon acute EVI1 repression in vivo and in vitro, profiled global EVI1 chromatin occupancy in human AML cell lines and primary patient-derived AML cells and performed comparative genome-wide CRISPR/Cas9-based loss-of-function screens in murine and human EVI1-driven AML. Results: Integration of these datasets revealed a conserved core of genes that is transcriptionally regulated by EVI1 in murine and human AML, among which we identified the ETS transcription factor ERG as the only dependency that is highly selective for EVI1-driven AML. Suppression of ERG specifically triggered cellular differentiation and apoptosis of EVI1-driven leukemia cells while other AML cell lines were unaffected. Strikingly, ectopic expression of ERG was sufficient to functionally rescue loss of EVI1 in EVI1-driven AML cells, suggesting that the major oncogenic function of EVI1 in AML is the aberrant activation of ERG. Summary/Conclusion: Interfering with the EVI1/ERG regulatory axis may provide entry points for the development of rational targeted therapies that are urgently needed for this group of AML patients.
Comprehensive benchmarking of CITE-seq versus DOGMA-seq single cell multimodal omics
Authors: Zhongli Xu, Elisa Heidrich-O’Hare, Wei Chen, Richard H. Duerr
Journal: Genome biology (2022)

Abstract The recently developed method TEA-seq and similar DOGMA-seq single cell trimodal omics assays provide unprecedented opportunities for understanding cell biology, but independent evaluation is lacking. We explore the utility of DOGMA-seq compared to the bimodal CITE-seq assay in activated and stimulated human peripheral blood T cells. We find that single cell trimodal omics measurements after digitonin (DIG) permeabilization were generally better than after an alternative “low-loss lysis” (LLL) permeabilization condition. Next, we find that DOGMA-seq with optimized DIG permeabilization and its ATAC library provides more information, although its mRNA and cell surface protein libraries have slightly inferior quality, compared to CITE-seq.
P734: DOWN-REGULATION OF RING1 AND YY1 BINDING (RYBP) LEADS TO EPIGENETIC OVEREXPRESSION OF ANTI-APOPTOTIC PROTEIN BCL2 IN MYELODYSPLASTIC SYNDROMES
Authors: F. Xu, X. Li, Q. He, L.-Y. Wu, Z. Zhang, C.-K. Chang
Journal: HemaSphere (2022)

Background: Excessive activation of oncogenes plays a crucial role in apoptosis resistance and disease progression to leukaemia in myelodysplastic syndromes (MDS). RYBP is a member of BCOR complex for epigenetic transcription repression, and also considered as an apoptosis-associated protein. However, the role of RYBP is still unclear in the myelodysplastic syndromes. Aims: To investigate the role of RING1 and YY1 binding (RYBP) in the myelodysplastic syndromes. Methods: The expression of RYBP mRNA and its clinical significance was analyzed in MDS patients. Lentivirus-mediated RYBP knockdown and overexpression were performed to investigate its biological function. The mechanism of RYBP in MDS development was investigated by cell functional assays, gene microarray and chromatin immunoprecipitation. Results: In this study, we found that reduced RYBP expression is observed in MDS patients and associated with high AML transformation. Overexpression of RYBP inhibits cell proliferation, and results in an increased cell apoptosis along with p53 activation in myeloid cell lines. However, knockdown of RYBP promotes cell proliferation, induces apoptosis resistance to etoposide and decitabine, and simultaneously reduces H2AK119ub1 level. Gene expression profile analysis identifies BCL2 as a possible target of RYBP. Further functional analysis shows that depletion of RYBP leads to transcription activation of BCL2 through removal of H2AK119ub1 at the promoter region of BCL2 gene. BCL-2 specific inhibitor ABT-199 significantly induces cell apoptosis in RYBP-depleted cells, and restores the apoptosis sensitivity to etoposide and decitabine. Summary/Conclusion: Reduced RYBP expression is frequent in MDS patients and associated with high AML transformation. RYBP inhibition leads to epigenetic overexpression of anti-apoptotic protein BCL2 in MDS, which contributes to apoptotic resistance of clonal cells and disease progression. BCL2 inhibitor may be considered as a candidate agent in advanced MDS.
S142: DECIPHERING THE COMPLEXITY OF T CELLS IN BLOOD AND LYMPH NODES OF PATIENTS WITH CLL BY INTEGRATIVE SINGLE-CELL RNA-SEQ AND MASS CYTOMETRY ANALYSES
Authors: L. Llaó Cid, J. Wong, M. Wierz, Y. Paul, S. Gonder, I. Fernandez Botana, T. Roider, S. Dietrich, D. Colomer, P. Lichter, M. Zapatka, E. Moussay, J. Paggetti, M. Seiffert
Journal: HemaSphere (2022)

Background: Abnormal distribution and impaired function of T cells are key features of chronic lymphocytic leukemia (CLL), a malignancy of mature B lymphocytes that develops in secondary lymphoid tissue and blood. These defects have been linked to failure of immune control and resistance to immunotherapy including immune checkpoint or CAR T-cell therapy. A better characterization of T cells and their loss of function in CLL will help to improve such treatment approaches. Aims: The goal of this study was an in-depth characterization of the T-cell compartment in blood and tissue samples of patients and mouse models with CLL to gain insights into the spectrum of phenotypes and transcriptional programs of T cells and the underlying mechanisms of their development. Methods: We performed mass cytometry (CyTOF) with a panel of 35 antibodies to characterize T cells in blood (n=8), bone marrow (n=3), and lymph nodes (n=21) of CLL patients, as well as reactive lymph nodes of non-tumor patients (n=13). We further generated single-cell transcriptome and T-cell receptor sequencing data of T cells from lymph nodes of CLL patients (n=5) and spleen samples of the Eµ-TCL1 mouse model (n=3), and performed integrative analyses of all data sets. Results: CyTOF analysis allowed for the identification and quantification of 15 clusters of CD4+ and 14 clusters of CD8+ T cells in blood, lymph node and bone marrow samples. T cells in blood and bone marrow were clearly distinct from lymph node derived cells, and several cell subsets showed a positively correlated abundance. A comparative analysis revealed an accumulation of several regulatory T-cell subsets, as well as T cells harboring an exhausted and dysfunctional phenotype in CLL lymph nodes. Single-cell transcriptome and T-cell receptor sequencing demonstrated the presence of clonally expanded and gradually exhausted T-cell clusters in human and murine CLL, and provided insights into the transcriptional programs and regulatory networks of these cell subtypes. Using CellPhoneDB (Efremova et al., Nature Protocols, 2020) and CellChat (Jin et al., Nature Communications, 2021) repositories, we identified novel ligand-receptor-interactions between CLL and T-cell clusters with impact on anti-tumor immune control which are currently tested in preclinical models for intervention therapy. Summary/Conclusion: Altogether, our study provides a detailed characterization of the T-cell compartment in CLL that helps us to understand T-cell exhaustion and suggests novel targets to improve immunotherapy for patients with CLL and likely also other malignancies. MZ, EM, JP and MS share senior authorship.
Insulin-like growth factor binding protein 7 promotes acute kidney injury by alleviating poly ADP ribose polymerase 1 degradation
Authors: Ju-tao Yu, Xiao-wei Hu, Qin Yang, Run-run Shan, Yao Zhang, Ze-hui Dong, Hai-di Li, Jia-nan Wang, Chao Li, Shuai-shuai Xie, Yu-hang Dong, Wei-jian Ni, Ling Jiang, Xue-qi Liu, Biao Wei, Jia-gen Wen, Ming-ming Liu, Qi Chen, Ya-ru Yang, Gui-yang Zhang, Hong-mei Zang, Juan Jin, Yong-gui Wu, Xiang Zhong, Jun Li, Wei Wang, Xiao-ming Meng
Journal: Kidney International (2022)
COVID-19 mRNA Vaccine Booster During Pregnancy Increases Maternal and Fetal Antibodies
Authors: Jennifer Abbasi
Journal: JAMA (2022)

Nir Kugelman, MD; Chen Nahshon, MD; Pninit Shaked-Mishan, PhD; Nadav Cohen, MD; Maayan Lahav Sher, MD; Maya Gruber, MD; Inbal Marom, MD; Avi Zolotarevsky, MD; Ofer Lavie, MD; Amit Damti, MD; Ariel Zilberlicht, MD; Mordehai Bardicef, MD; Reuven Kedar, MD
P1468: SLEEP DISORDERED BREATHING IN SICKLE CELL DISEASE: RELATION TO PULMONARY HYPERTENSION AND STROKE
Authors: N. B. E.-D. Farghal, A. Tantawy, F. S. E. Ebied, N. El-Sherif, N. Salah Eldeen, N. Soliman, S. Makkeyah
Journal: HemaSphere (2022)

Background: Sleep disordered breathing (SDB) is a common underdiagnosed sequela of sickle cell disease (SCD) characterized by daytime sleepiness, behavioral changes, and cognitive deficits. Nocturnal desaturations have also been linked to the frequency of vaso-occlusive crises (VOCs), acute chest syndrome (ACS), cardiac abnormalities, central nervous system (CNS) events, and nocturnal enuresis. Aims: To determine the frequency of SDB in patients with SCD and its association with SCD-related complications. Methods: Thirty children and adolescents with SCD were evaluated using overnight polysomnography after completing the modified STOP-Bang questionnaire. Transcranial doppler (TCD) and echocardiography with assessment of tricuspid regurge velocity (TRV) were performed. Data of SCD, and related complications were collected from the patients’ records. Results: The median age of the studied cohort was 10.2 years (range 6-17 years), with male: female ratio 1.7:1. Six patients (20%) had high-risk for obstructive sleep apnea (OSA), nine (30%) had intermediate risk, and fifteen (50%) at low risk. Sleep apnea, defined as respiratory disturbance index (RDI) > 1 event/hour, was found in 18/30 (60%) of patients (14 males and 4 females). Patients with RDI > 5 (moderate to severe OSA) had significantly higher TRV (p = 0.007) and left MCA flow velocity (p = 0.049) when compared to those with RDI < 5. Although right MCA flow velocity was higher in the moderate to severe OSA group, this did not reach statistical significance (p = 0.054). Other variables including BMI-SDS (0.07), presence of cardiac dysfunction (p = 0.26), history of stroke (p = 0.17), or presence of nocturnal enuresis (p = 0.33) were comparable between both groups. Patients with RDI > 5 were at higher risk of OSA according to the modified STOP-Bang questionnaire (p = 0.02). RDI positively correlated with TRV (r = 0.53, p = 0.003), right MCA flow velocity (r = 0.45, p = 0.013) and left MCA flow velocity (r = 0.55, p = 0.002), while it showed negative correlation with BMI-SDS (r = -0.48, p = 0.008). Summary/Conclusion: Sleep apnea is a common problem in patients with SCD associated with risks of pulmonary hypertension and alterations in cerebral blood flow which highlights the need for early diagnosis and management.
P1177: PROGNOSTIC VALUE OF TP53 VARIANTS IN CHILDREN WITH MATURE B-CELL LYMPHOMA TREATED ACCORDING TO REDUCED-INTENSITY B-NHL-2010M PROTOCOL
Authors: V. Egor, A. Yuliya, K. Brenning, A. Itov, D. Abramov, A. Sharlai, M. Senchenko, D. Konovalov, G. Novichkova, N. Miakova
Journal: HemaSphere (2022)

Background: Reduced-intensity rituximab-based therapy leads to long-term remission in more than 80-85% of pediatric patients with B-cell non-Hodgkin lymphoma (B-NHL), but in case of relapse or refractoriness the prognosis in poor with less then 20% survival rate. Therefore, the identification of adverse prognostic factors is critically important. Recent data show that the status of the TP53 gene may be of prognostic value in children with B-NHL. We evaluated the clinical significance of TP53 abnormalities in children with B-NHL enrolled in the Russian-Belorussian B-NHL-2010mab multicenter clinical trial. Aims: To investigate the prognostic value of TP53 gene status in pediatric B-NHL receiving reduced-intensity therapy Methods: Due to reference status of pathology department in Dmitry Rogachev National Medical Research Center for Pediatric Hematology, Oncology, and Immunology, samples from 79 pediatric B-NHL patients (77 with Burkitt lymphoma and 2 with diffuse large B-cell lymphoma) treated according to B-NHL-2010mab protocol in 2012-2021 were included in this study. The median age was 9 years (range 2-17 years), m:f ratio was 6:1. 19 patients (24%) had limited stage and 60 patients (76%) had advanced-stage of disease. DNA was extracted from FFPE tissue, TP53 variants were detected using Sanger sequencing of exons 5 to 8 according to the International Agency for Research on Cancer (IARC) protocol. B-NHL samples were obtained following informed consent from participants or their parents/guardians. Results: Median follow up was 16 months (range 5-117 months). The 5-year event free and overall survival for all patients was 86,3% (95%CI=78, 3-94%) and 86,5% (95%CI=78,3-94,8%) respectively. DNA suitable for sequencing was obtained from 66 samples. TP53 pathogenic variants were present in 26% of cases and were associated with a significantly inferior event free and overall survival compared to those without a TP53 abnormality: 45,3% (95%CI = 21-69,6%) vs 97,9% (95%CI=93,9-100%) (p < 0.001) and 47,1% (95%CI=21,8-72,4%) vs 97,9% (95%CI= 93,9-100%) respectively (p = 0.001). 13 patients with unknown TP53 status are alive without relapsed of disease. Summary/Conclusion: Our findings show the independed prognostic value of TP53 pathogenic variants in pediatric B-NHL patients treated with rituximab-based reduced-intensity therapy. Therefore, given the poor survival rate of patients with TP53 mutations, this marker can be used to define high risk groups within pediatric B-NHL, those who need new therapeutic approaches to achieve better results. It is necessary to study this prognostic factor in large groups of patients.
Promoting the Values for Surrogate Decision-making
Authors: David Wendler
Journal: JAMA (2022)

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